Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression
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Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. / Erice, O; Labiano, I; Arbelaiz, A; Santos-Laso, A; Munoz-Garrido, P; Jimenez-Agüero, R; Olaizola, P; Caro-Maldonado, A; Martín-Martín, N; Carracedo, A; Lozano, E; Marin, J J; O'Rourke, C J; Andersen, J B; Llop, J; Gómez-Vallejo, V; Padro, D; Martin, A; Marzioni, M; Adorini, L; Trauner, M; Bujanda, L; Perugorria, M J; Banales, J M.
In: B B A - Reviews on Cancer, Vol. 1864, No. 4, Part B, 04.2018, p. 1335-1344.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression
AU - Erice, O
AU - Labiano, I
AU - Arbelaiz, A
AU - Santos-Laso, A
AU - Munoz-Garrido, P
AU - Jimenez-Agüero, R
AU - Olaizola, P
AU - Caro-Maldonado, A
AU - Martín-Martín, N
AU - Carracedo, A
AU - Lozano, E
AU - Marin, J J
AU - O'Rourke, C J
AU - Andersen, J B
AU - Llop, J
AU - Gómez-Vallejo, V
AU - Padro, D
AU - Martin, A
AU - Marzioni, M
AU - Adorini, L
AU - Trauner, M
AU - Bujanda, L
AU - Perugorria, M J
AU - Banales, J M
N1 - Copyright © 2017. Published by Elsevier B.V.
PY - 2018/4
Y1 - 2018/4
N2 - BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated.METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro.RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism.CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.
AB - BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated.METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro.RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism.CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.
KW - Journal Article
U2 - 10.1016/j.bbadis.2017.08.016
DO - 10.1016/j.bbadis.2017.08.016
M3 - Journal article
C2 - 28916388
VL - 1864
SP - 1335
EP - 1344
JO - Biochimica et Biophysica Acta - Reviews on Cancer
JF - Biochimica et Biophysica Acta - Reviews on Cancer
SN - 0304-419X
IS - 4, Part B
ER -
ID: 183574630